There are known metallocene complexes containing titanium, vanadium, niobium and molibdenum as a metal ion, which are active against a variety of tumor cell lines such as B16 melanoma, colon 38 carcinoma, Lewis lung carcinoma, etc. It has been shown that the activity of vanadium complexes related to the formula Cp.sub.2 VCl.sub.2 where C.sub.p is cyclopentadiene, against human epidermoid (HEP-2) tumor cells in vitro and against mouse tumor cells, is similar to that of cis-platin (Murthy M. S. et el. Proc. Am. Assoc. Cancer Res. 1986, 27, 279). A study which was carried out with a corresponding molibdenum compound, supports the possibility that these complexes are binding 5'-phosphate terminated polynucleotides, thus inhibiting DNA replication, by a mechanism which different from that of cis-platinum complexes (Kon, L. Y. et al. J. Am. Chem. Soc. 1991, 113, 9027).
Titanocene dichloride, one of the first metallocene compounds which was tested, was found to be indeed a very reactive anti-tumor reagent. Due to its rapid hydrolysis to the corresponding dihydroxy derivative, it is quite reasonable to assume that this dihydroxy titanocene is the actual drug. Accordingly, many references can be found describing titanocene compounds which were tested in an attempt to possess an improved cytotoxity. Examples of such compounds include halides, pseudohalides, carboxylates, and phenolates. However, no significant improvement over titanocene dichloride in the antitumor activity has been achieved.
The metallocene diacido complexes, having the general formula (C.sub.5 H.sub.5).sub.2 MX.sub.2 are characterized by the following structural features:
The geometry of the complexes is that of a distorted tetrahedron. PA1 The complexes contain two uninegative acido ligands X coordinated to the central metal atom and arranged in adjacent "cis-like" position. PA1 The sites of the other two ligands are occupied by two anionic cyclopentadienyl rings.
Attempts to modify the cyclopentadienide rings lead to a decreased biological activity.
In a very recent U.S. Pat. No. 5,002,969 there are described cytostatic pharmaceutical compositions based on titanocene complexes. A group which is present in all these complexes is an amino or substituted amino bound to the titanoceno moiety. These compounds are obtained by a reaction between a titanocene dihalogenide and an amino phenol, lithium aminophenolate, or lithium amino thiophenolate. There is mentioned that the compounds have a better solubility in water than titanocene dichloride, fact which improves their application and dosing. Other titanocene complexes which were described, differ by their ionic character from the neutral titanocene compounds. Most of them correspond to the general formula [(C.sub.5 H.sub.5).sub.2 TiXL].sup.+ Y.sup.- where X and Y are anions and L is a neutral donor molecule. These ionic titanocene complexes are characterized by their improved water solubility compared with the neutral titanocene compounds.
It is an object of the present invention to provide novel titanocene derivatives. It is another object of the present invention to provide novel titanocene derivatives which possess a superior cytotoxic activity than the cis-platinum complexes.